喜樹鹼具良好的抗癌活性，其水溶性差，藉化學修飾的衍生物有Topotecan及Irinotecan已在臨床上使用，由於對腫瘤無專一性，會導致嚴重的副作用，因此，先期本實驗室藉腫瘤處會大量表現β-葡萄糖醛酸?，設計合成兩個喜樹鹼葡萄糖醛酸前驅藥(9-ACG及10-HCG)，前驅藥只在癌細胞處活化達到標靶作用。據研究顯示，9-ACG與10-HCG對喜樹鹼的水溶性分別增加1800倍與20倍，9-ACG與10-HCG之細胞毒性分別比喜樹鹼降低30倍與10倍，而10-HCG之酵素活化效率為9-ACG的520倍，藉電腦計算結果顯示，乃因10-HCG的醚類鍵結與酵素間有較好的鍵結所致。本研究中，為提升10-HCG的水溶性並降低細胞毒性，設計在10-HCG的苯基加入模擬Irinotecan之N-methylpiperazine基團，合成目標物10-HCPG，期待它能增加親水性、在血液中穩定、低細胞毒性、酵素親和力佳，以及對腫瘤有專一性。 Camptothecin has good anti-cancer activity, and current clinical use of two derivatives are Topotecan and Irinotecan which improve poor water solubility of Camptothecin by chemical modification. However, the lack of drugs specificity of tumor will cause severe side effects. Therefore, our laboratory designed and synthesized two glucuronide prodrugs of Camptothecin (9-ACG and 10-HCG) which will mainly be activated at tumor site expressing large number of β-glucuronidase. According to previous studies, 9-ACG and 10-HCG was 1800 and 20 times soluble than 10-HCG, respectively; 9-ACG and 10-HCG was 30-fold and 10-fold less toxic than the parent drug to cells, respectively; Enzyme kinetic studies showed that β-glucuronidase exhibited 520 times higher catalytic ef?ciency for 10-HCG than for 9-ACG, and molecular modeling studies predicted that 10-HCG would have a higher binding af?nity to enzyme than 9-ACG. In this study, we design and synthesize the target compound 10-HCPG by creating N-methyl piperazine on the benzyl group of 10-HCG, expect for good water solubility, stable in blood, low cytotoxicity, good affinity with β-glucuronidase and specific to tumor cells.
